(a) Field of the Invention
This invention in its broadest aspect relates to inhibitors of metabolic pathways. In particular, the invention relates to novel compounds of Formula I, which are inhibitors of leukotriene D.sub.4 (LTD.sub.4) and which therefore are useful to prevent or alleviate the symptoms associated with LTD.sub.4, such as allergic reactions, particularly asthma, see M. Griffin et al., N. Engl. J. Med., 308, 436 (1983); inflammatory conditions; and coronary vasoconstriction.
LTD.sub.4 is a product of the 5-lipoxygenase pathway and is the major active constituent of slow reacting substance of anaphylaxis (SRS-A), a potent bronchoconstrictor that is released during allergic reactions. See R. A. Lewis and K. F. Austen, Nature, 293, 103-108 (1981). When administered to humans and guinea pigs, LTD.sub.4 causes bronchoconstriction by two mechanisms: (1) directly by stimulating smooth muscle; and (2) indirectly through release of thromboxin A.sub.2, which causes contraction of respiratory smooth muscle. Because antihistamines are ineffective in the management of asthma, SRS-A is believed to be a mediator of the bronchoconstriction occurring during an allergic attack. LTD.sub.4 may also be involved in other inflammatory conditions such as rheumatoid arthritis. Furthermore, LTD.sub.4 is a potent coronary vasoconstrictor and influences contractile force in the myocardium and coronary flow rate of the isolated heart. See F. Michelassi et al., Science, 217, 841 (1982); J. A. Burke et al., J. Pharmacol. and Exp. Therap., 221, 235 (1982).
(b) Prior Art
Certain 2-alkylated chromanon-2-yl derivatives have been disclosed in the prior art. European Patent Application No. 0079637 and U.S. Application Ser. No. 06/560355, the latter having the same assignees as the present invention, disclose 2-alkylated chromanon-2-yl alkanoic acids. Since none of the compounds claimed in the present invention possesses a carboxylic acid function, they are distinguishable from chromanon-2-yl alkanoic acids of the prior art.
By combination of elements disclosed and claimed, Ser. No. '355 appears also to disclose certain 2-alkylated chromanon-2-yl alkanediols and ketoalkanols related to those claimed herein. However, the particular combination of elements that are characteristic of this invention, particularly the 2-alkyl-2-ketoalkanols and 2-alkyl-2-alkanediols, are not described in the prior art, nor are enabling methods for the preparation of compounds of this invention described. As described in Ser. No. '355, the side-chain keto group (or a hydroxymethylene group subsequently formed by reduction of the keto group) must always be attached directly to the chromanone nucleus. (That is, in Formula I, below, Z must be attached directly to the 2-position of the chromanone nucleus, with no intervening methylene carbon atoms). The compounds of this invention always possess an intervening alkylene chain. Moreover, all prior art compounds in Ser. No. '355 having a side-chain ketone function must be formed as acylation products of 2-carboxychromanones and not of 2-alkylchromanones. In contrast, the compounds of this invention are formed by a ring closure (see Scheme A, below) that does not require a 2-carboxyl function and permits the ketone group to be separated from the chromanone ring.